Abstract 3426: The Generation Of Biosynthetic Small Caliber Grafts With Improved Patency Using Autologous Genetically Modified Endothelial Cells.

Introduction: Seeding polymer-based synthetic vascular grafts with endothelial cells (EC) improves grafts biocompatibility and consequently grafts patency. EC adhesion and survival on the synthetic polymer remains a considerable challenge. We used pseudo-typed retroviral vectors to modify EC to co-express fibulin-5 and VEGF 165 and created a unique EC phenotype with increased adhesion and enhanced proliferation and used these cells to seed vascular grafts. Methods: Polymer-based grafts seeded with autologous venous EC transduced to co-express fibulin-5 and VEGF 165 were implanted in the carotid arteries of the donor sheep. 18 grafts (8 seeded grafts with EC co-expressing fibulin-5 and VEGF, 6 seeded with control EC and 4 bare grafts) were implanted for two week in nine sheep. Six months studies were performed on 18 grafts (6 study, 6 seeded with control EC and 6 bare) implanted in 18 sheep. Histological studies for cell adhesion, intra-luminal thrombosis and transgene expression were tested in implanted grafts after angiography. Results: At two weeks all 8 grafts seeded with EC co-expressing fibulin-5 and VEGF were patent with no significant thrombosis and 73% coverage by seeded EC, while 3/10 control grafts were thrombosed and only 30% of seeded unmodified EC remained on grafts luminal surface. At 6 months, 5/6 grafts seeded with EC co-expressing fibulin-5 and VEGF were patent while 9/12 control grafts (6 bare, 6 seeded with unmodified EC, p<0.04) were occluded. At 6 months, the genetically modified cells were identified on the graft surface and these grafts had improved EC coverage and reduced intra-luminal neo-intima and thrombosis. No local or systemic side effects were attributed to the implanted grafts. Conclusion : Polymer-based vascular grafts seeded with EC transduced to co-express fibulin-5 and VEGF have lower propensity to thrombosis and improved patency. Use of grafts seeded with EC co-expressing fibulin-5 and VEGF provides a potentially clinically relevant method for small caliber blood vessel engineering.